1. Field of the Invention
The invention relates to a tear substitute for the external treatment of the eye.
2. Prior Art
Tear substitutes are used in the treatment of diseases of the eye, such as common keratoconjunctivitis sicca (so-called “dry eye”). Dry eye can be the result of different causes. The most frequent causes include reduction in tear production in the elderly, rheumatic or internal diseases (such as polyarthritis, diabetes and thyroid disease), diseases in which antibodies are raised against the body's own physiological substances (Sjörgren's disease, Lupus erythematodes, sclerodermia), skin diseases, hormonal changes, neuroparalysis (such as after a stroke, defective position of the eyelid, decortication of tear glands), ingestion of certain drugs (such as β blockers, birth control pill, soporifics and tranquilizers), nutritional deficiency, climatic influences (heat, dry environmental air, season, air conditioners), environmental pollution (ozone, dust, solvent vapors, etc.), working in front of monitors, and chronic use of vessel contracting eyedrops (so-called whiteners). Furthermore, such eye diseases are also caused, but less frequently, by autoimmune diseases, diseases of the hematopoietic system, local eye diseases such as inflammation and trauma of the tear glands or hereditary diseases. The resulting dysfunctions impair or prevent the formation of a normal tear film, which has an exceedingly complicated structure in its natural form. There are essentially three components which participate in the formation of the tear film:
An internal mucin layer which covers the epithelial surface, followed by a middle aqueous layer, and a thin, external lipid layer. The mucin layer here functions as an adhesive component for the wetting of the cornea. The aqueous component moisturizes the cornea and it has a cleaning and protective function. The lipid component prevents evaporation of the aqueous component and prevents a quick runoff of the tear film.
Only an intact tear film can guarantee the full functionality of the eye surface over time, and, in addition to the mentioned defects, properties which reduce abrasion, antibacterial properties, and the oxygen supply of the cornea can be of importance. The above-mentioned components of tears are continuously produced. The formation of a thin tear film over the cornea occurs spontaneously with each blink of the eyelid, as, during the downward movement of the upper lid, the external lipid layer of the tear film is compressed between the lid margins, where the aqueous layer essentially remains in its position. As soon as a part of the production of the tear components is interrupted or disturbed, or there is a mechanical obstacle to the formation of the tear film as a result of the blinking of the eyelid, corresponding complaints arise from, for instance the so-called sand grain effect to massive visual disorders, which in extreme cases, can lead to blindness as a result of irreversible damage to the cornea.
As there are a multitude of possible causes of “dry eye” and as the problem of the tear film [formation] is complex, a multitude of treatment agents are known from the state of the art. In this context, examples are the patents EP 698 388, DE 195 11 322, DE 43 03 818, EP 801 948, WO 97/45102, and WO 96/33695.
In the above-mentioned patents, descriptions are essentially provided of treatment agents which, as a result of introduction into the conjunctival sac, replace one or more missing components of natural tear film. The replacement is here carried out using substances which, having an appropriate retention time, take over the protective and abrasion-reducing functions, and possess the same or at least similar properties as the components to be substituted. The treatment agent which is commercially available under the trade name “Liposic,” for example, constitutes an attempt to duplicate all the natural tear components in a so-called three-dimensional tear.
The liquid treatment agents which are known from the state of the art, however, all present the drawback of having a relatively short residence time on the cornea. As a result, the treatment agent must be introduced at regular intervals into the eye, which can be very inconvenient and unpleasant for the patient. In the known gel form treatment agents, this drawback is at least partially avoided. However, in the case of gel form treatment agents, it was shown to be difficult to supply sufficient oxygen to the cornea.
In the patents EP 089 815 and EP 112 658, ophthalmological treatment agents for lubrication and protection of the eye surface are proposed which contain a perfluorocarbon or a substituted derivative thereof. The substantial advantages compared to conventional treatment agents that are mentioned are here the immiscibility with water and the high gas dissolution capacity, particularly for oxygen.
Because of the known high oxygen dissolution capacity of fluorocarbons, the treatment agent described in the above patents is said to guarantee a sufficient oxygen supply for the cornea. In addition, because of the high density of the perfluorocarbons, a long residence time on the cornea is said to be possible because the compounds are said to become enriched due to their high specific weight. Moreover, it is claimed that, because of the insolubility of the treatment agent in water, the use of preservatives could be omitted.
However, the drawbacks of these perfluorocarbon-containing treatment agents are that an intact mucin layer and sufficient secretion of lipids must be guaranteed to allow sufficient functionality of the agent on the cornea. Additional drawbacks result from impaired vision as a result of the formation of streaks, as well as the risk of obstructing the tear drainage ducts, caused by the immiscibility of the perfluorocarbons with water. Moreover, the immiscibility of perfluorocarbon and water, as well as the large interfacial tension between aqueous and perfluorocarbon-containing areas lead to the formation of diffusion barriers, which prevents a sufficient supply [of oxygen] to the cornea.
In addition, different forms of fluorogels are known from the state of the art, which were also proposed for medicinal applications. From U.S. Pat. No. 5,573,757 and EP 340 079 as well as WO 97/03644, polyaphron gels are known whose structure is stabilized by fluorinated surfactants. The structure and the properties of polyaphron gels are described, for example, in Chapter 8 of Foams and Biliquid Foams-Aphrons, F. Sebba, John Wiley, 1987.
Fluorogels as such, in general, present a pronounced viscoelasticity. These substances therefore are not suitable for an extraocular treatment of eye diseases, because the absence of a pronounced property of film formation does not allow an even distribution and wetting of the cornea.
Therefore, the problem of the present invention is to provide a tear substitute which is tolerated over the long term, which allows even wetting of the cornea, which presents a long retention time on the eye surface, and which guarantees the supply of oxygen and water-soluble nutrients to the cornea.